Single Oocyte Transcriptome Analysis and Genome Engineering Uncovers Regulators of Meiotic Progression - AWARD NOMINEE

The main cause for infertility, natural-miscarriages and congenital defects is mis-segregation of chromosomes during oogenesis. These mis-segregations increase exponentially towards the end of the fourth decade of women’s life. To study the processes that leads to these failures we turned to a simpler system, the nematode C. elegans, a leading model organism in both meiosis and aging. We found that within days of arrest, C. elegans arrested oocytes show precautious separation of chromosomes and sister chromatids, similar to aged human oocytes. High-resolution microscopy indicated that the chromosomes in aged oocytes have aberrant structure, which could lead to the failed segregations. To uncover the entire genetic program of oogenesis we analyzed the transcriptome of sequential segments of the worm’s gonad, in which the cells are arranged in a perfect order from the oogonial stem-cell to the mature oocyte. We found that most genes fall into two reciprocal expression profiles that switches expression levels at late pachytene. We observed that while the X chromosome is silenced throughout the first half of the gonad, some genes escape this control and are highly expressed throughout the germline. Using this database and an RNAi screen we found genes that are involved in meiotic entry, oocyte quality control, and restructure of the chromosomes. Deletion of one them, F52H3.4, led to major changes in these proceses. Put together, by using a simple and powerful model organism and high-throughput transcriptomics, we now move towards deciphering the genetic network that facilitate the meiotic divisions throughout the female fertility term.